fMRI Spatial Context and Fear Conditioning

Purpose:

Background:
- Fear is a normal response to a threat. Learning fear can be helpful sometimes. For people
with anxiety disorders, fear can be long-lasting and too intense. Researchers want to study
how people become fearful of situations. They want to understand how the brain learns when it
is helpful to feel fear and when it is not.
Objective:
- To better understand brain processes related to fear and anxiety.
Eligibility:
- Right-handed adults ages 18 50 with generalized anxiety disorder, panic disorder, social
anxiety disorder, or post-traumatic stress disorder.
- Right handed volunteers ages 18-50 without psychiatric disorders.
- And free of psychiatric medication for 2 weeks
Design:
- Participants will first be screened under another protocol.
- Participants will play a video game inside a magnetic resonance imaging (MRI) scanner.
The scanner is a metal cylinder It is surrounded by a strong magnetic field.
Participants will lie on a table that can slide in and out of the scanner. A device
called a coil will be placed over the head.
- During the scan, participants may play a virtual reality video game. Game instructions
will be explained before they enter the scanner.
- While playing the game, participants will wear 2 electrodes on their fingers. These
measure sweat on the skin. They will also have 2 small electrodes attached to the left
hand. These can give brief mild electrical shocks.
- Participants will be asked questions when playing the game during the scan.
- Before and after the scan, participants will fill out questionnaires about their
emotions. They may complete questionnaires online while at the clinic.

Study summary:

Objective:
To examine the processes involved in distinguishing between threatening and safe conditions,
we aim to investigate the neural bases of contextual fear learning using functional magnetic
resonance imaging (fMRI). To do this, we will study behavioral, physiological, and brain
responses as aversive stimuli are encountered in a virtual environment, and will explore how
fear-related responses depend on the surrounding environment. In addition, we will examine
how these responses differ in clinical anxiety.
We are interested in studying Pavlovian aversive context conditioning in healthy controls and
patients with anxiety disorders. We will examine the extent to which participants learn to
discriminate between dangerous and safe virtual contexts, and how this learning maps to the
neural networks underlying anxiety and context coding. We expect successful learning of the
contextual fear response in healthy controls, as evidenced by differential skin conductance
response and neural activation to safe vs. threat context. Accordingly, we anticipate higher
neuronal activity in the hippocampus, prefrontal cortex, and amygdala. These findings will be
accompanied with increased hippocampus-prefrontal cortex connectivity during approach and
exploration of the dangerous context, and increased amygdala activation during anticipation
of shock in the dangerous context. Physiologically, SCR will increase in threat context
compared to safe context. However, anxious patients are expected to fail to learn to
differentiate safe from threat context, exhibiting increased SCR and neural activation in
both safe and threat contexts, an index of contextual generalization of fear. Particularly,
the lack of contextual fear discrimination in anxious patients will be associated with weaker
hippocampal activation to contextual learning. To examine differential context fear
conditioning, we will use a virtual reality (VR) paradigm. VR provides an optimal way to
probe spatial navigation and simulates context. The VR task presents an outdoor space, which
comprises a dangerous (probabilistic electrical shocks) and a safe (no shocks) location.
Healthy controls and patients with anxiety disorders will be compared on their physiological
and neural reactivity during task performance. Preliminary psychophysiological data suggest
that the proposed procedure is an effective way to promote different responses to a safe and
dangerous spatial location. Hence, we anticipate that this procedure will allow us to examine
brain correlates of differential contextual fear responses in humans and compare them between
healthy participants and patients diagnosed with an anxiety disorder.
Study population:
Two study populations, healthy volunteers and patients diagnosed with an anxiety disorder
(generalized anxiety disorder (GAD), social anxiety disorder (SAD), panic disorder, and
post-traumatic stress disorder) will complete the protocol. Participants will be adult males
and females, aged 18 to 50 years.
Design:
This fMRI study will compare performance, physiological and neural measures between healthy
adults and patients with anxiety disorders, who perform a threat VR task in the scanner.
The VR task entails navigating in a virtual outdoor environment, which, unbeknownst to the
participants is divided into a safe and a dangerous context, which are recognizable by
environmental characteristics (e.g., mountain, clouds). The dangerous context is associated
with probabilistic shocks, which are never encountered in the safe context. Participants
learn about these two contexts as they collect flowers (cues), one at a time, in either
context. In the dangerous context, the flowers are associated with 50% chance of a shock
Outcome measures:
The primary outcome measures will be the cerebral fMRI blood-oxygen-level dependent (BOLD)
responses to three events: (1) shock anticipation: after collecting the cues (flowers) during
anticipation of a potential shock, (2) context exploration: as participants navigate in the
threat context or safe context in between trials (which start when a flower appears in the
environment), and (3) cue approach: during approach towards the flower, in the threat or safe
context. The secondary outcome measures will consist of the changes in psychophysiological
responses, such as SCR, heart rate, pupil dilatation, and respiratory rate, which will
validate fear responses.

Criteria:

- INCLUSION CRITERIA:
- Ages 18-50
- Subjects able to give their consent
- Right handed
- Patients only: a primary diagnosis of GAD, panic disorder, SAD, or PTSD according to
the Structured Clinical Interview for DSM-IV-TR
EXCLUSION CRITERIA:
- Non-English speaking individual
- Any significant medical or neurological problems (e.g. cardiovascular illness,
respiratory illness, neurological illness, seizure, etc.)
- High or low blood pressure (SBP>140 or SBP<90; SDP<50 or SDP>90)
- Alcohol/drug abuse in the past year or lifetime alcohol or drug dependence according
to the Structured Clinical Interview for DSM-IV-TR
- Medications that act on the central nervous system (e.g., Lorazepam, Codeine) and thus
may interfere with the interpretation of study results. Specific exclusionary drug
classes include but are not limited to: (opioid analgesics, DA receptor agonists,
anticholinergics, MAO inhibitors, COMT inhibitors, as well as any illicit substances)
- Pregnancy or positive pregnancy test
- Neurological syndrome of the wrist (e.g., carpal tunnel syndrome, cubital tunnel
syndrome, etc.)
- Positive urine toxicology screen
- IQ <80
- Participants who report getting severe motion sickness, especially by playing video
games
- Any medical condition that increases risk for fMRI:
- Any metal implants (clips, screws, plates, pins, etc) or metal fragments cause by
injuries or metal working
- Any sort of medical implants (aneurysm clips, pacemaker, insulin pump, Hickman
line, etc.)
- Permanent eye liner and tattoos above the neck
- Patients who have difficulty lying flat on their back for up to 60 min in the
scanner
- Participants who are uncomfortable in small closed spaces (have claustrophobia)
and would feel uncomfortable in the MRI machine
Additional Exclusion Criteria for Healthy Volunteers:
- Current or past Axis I psychiatric disorders as identified with the Structured
Clinical Interview for DSM-IV-TR, non-patient edition (SCID-np)
- Current use of psychotropic medications (i.e. fluoxetine (Prozac), fluvoxamine
(Luvox), sertraline (Zoloft), paroxetine (Paxil), citalopram (Celexa) or escitalopram
(Lexapro), etc.).
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Additional Exclusion Criteria for Patients:
- Patients who are currently on psychotropic medications. (Patients are required to be
free of all psychotropics medication (i.e. fluvoxamine (Luvox), sertraline (Zoloft),
paroxetine (Paxil), citalopram (Celexa) or escitalopram (Lexapro), etc.) for 2 weeks,
5 weeks for fluoxetine prior to testing. Patients will not be taken off medications
for the purpose of the study)
- Patients will be excluded if they have a current or past history of any psychotic
disorder, delirium, dementia, amnestic disorder, cognitive disorder not otherwise
specified, any of the pervasive developmental disorders, or mental retardation
- Patients who have a primary diagnosis of major depressive disorder.